Defining the impact of pre-existing memory T cells in human immunity

定义预先存在的记忆 T 细胞对人体免疫的影响

• 批准号: 9759761
• 负责人: Laura Su
• 金额: $ 52.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759761
• 关键词: Address; Adult; Antigens; Area; Autoimmunity; Biology; CD4 Positive T Lymphocytes; Cells; Clone Cells; Cytometry; Data; Development; Disease; Environment; Exhibits; Exposure to; FOXP3 gene; Foundations; Frequencies; Future; Gene Expression Profile; HIV; Health; Human; Immune; Immune response; Immune system; Immunity; Immunization; In Vitro; Infection; Interferon Type II; Interleukin-13; Interleukin-17; Interleukin-2; Label; Laboratory mice; Malaria; Malignant Neoplasms; Maps; Memory; Modeling; Mus; Parents; Peptide/MHC Complex; Peptides; Phenotype; Population; Primary Infection; RNA; Reagent; Research; T cell response; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Thymus Gland; Time; Tracer; Tuberculosis; Vaccination; Vaccines; Viral Antigens; Yellow fever virus; cross reactivity; effector T cell; experience; experimental study; germ free condition; high dimensionality; improved; in vivo; insight; malaria infection; microbial; mouse model; novel; pathogen; response; vaccine development; vaccine efficacy; volunteer

Project Summary Globally, more than 18 million people are infected with HIV, 10.4 million people are infected with tuberculosis, and over 200 million people become infected by malaria in a single year. There is a critical unmet need for vaccines against these infections and studies using mouse models have not yielded effective vaccines. The development of a functional memory response that enables the immune system to react quickly and robustly to previously experienced pathogens is the single most important factor for vaccine efficacy. Defining the mechanisms by which memory T cell responses are generated in humans is essential for developing efficacious vaccines. Previous studies in laboratory mice have shown that primary T cell responses to novel antigens originate from naïve T cells. However, mice maintained under specific pathogen-free conditions are vastly different from humans in the extent of their microbial exposure. Our lab was the first to describe that human adults possess pre-existing memory phenotype (TMP) CD4+ T cells specific for viral antigens to which they have never been exposed. We further demonstrated that nearly a quarter of HIV-reactive T cell clones isolated from uninfected people also respond to unrelated microbial peptides, suggesting that these TMP cells are broadly cross-reactive to many different antigens. The development of TMPs likely reflects the cumulative exposure to environmental antigens following thymic development and these cells may be the earliest cells to respond during a primary infection. Here, we will build on these foundations and use yellow fever virus (YFV) vaccination as a model to test the hypothesis that pre-primed TMP cells generate potent effectors and preferentially give rise to post-vaccination memory T cells in humans. We will use a specific cell-labeling reagent called tetramers to tag T cells that recognize YFV antigens before vaccination and at multiple times after vaccination. This will allow us to trace YFV-reactive T cells directly ex vivo as they evolve following vaccination. Specifically, we will address the following questions: (1) does TMP cells have a greater functional diversity and plasticity compared to classic memory T cells; (2) does the abundance or the composition of TMP cells predict the rate and the magnitude of the effector response; (3) does TMP cells preferentially give rise to post-vaccination memory T cells? This study will reveal basic paradigms of how pre- existing memory precursors impact the potency and durability of CD4+ T cell immunity in vaccination. Understanding how the environment conditions the human T cell repertoire to influence later responses extends beyond vaccine efficacy and is broadly relevant to many areas of human health, including infection, autoimmunity, and cancer surveillance

项目摘要 全球有1 800多万人感染艾滋病毒，1 040万人感染结核病， 一年之内就有2亿多人感染疟疾。有一个关键的未满足的需要， 针对这些感染的疫苗和使用小鼠模型的研究尚未产生有效的疫苗。的 功能性记忆反应的发展，使免疫系统能够迅速和有力地反应， 先前经历的病原体是疫苗效力的最重要因素。定义 记忆T细胞反应在人类中产生的机制对于发育至关重要。 有效的疫苗先前在实验室小鼠中的研究表明，原发性T细胞对新的 抗原来源于幼稚T细胞。然而，在特定的无病原体条件下维持的小鼠， 在微生物暴露的程度上与人类有很大的不同。我们的实验室是第一个 成人具有对病毒抗原特异性的预先存在的记忆表型（TMP）CD 4 + T细胞， 他们从来没有接触过。我们进一步证明，近四分之一的HIV反应性T细胞 从未感染者中分离的克隆也对不相关的微生物肽有反应，这表明这些TMP 细胞对许多不同的抗原具有广泛的交叉反应性。TMP的发展可能反映了 胸腺发育后累积暴露于环境抗原，这些细胞可能是 在初次感染期间最早的细胞作出反应。在这里，我们将建立在这些基础上， 发热病毒（YFV）疫苗接种作为模型来检验预致敏的TMP细胞产生有效的 在人类中，免疫调节因子是免疫调节效应物，并且优先产生疫苗接种后记忆T细胞。我们将使用一个 一种称为四聚体的特异性细胞标记试剂，用于在接种疫苗前标记识别YFV抗原的T细胞， 在接种疫苗后多次。这将使我们能够直接离体追踪YFV反应性T细胞，因为它们 接种疫苗后的变化。具体而言，我们将解决以下问题：（1）TMP细胞是否具有 与经典记忆T细胞相比，具有更大的功能多样性和可塑性;（2）丰度或 TMP细胞的组成预测效应器反应的速率和幅度;（3）TMP细胞是否 优先产生疫苗接种后的记忆T细胞？这项研究将揭示如何预- 现有的记忆前体影响疫苗接种中CD 4 + T细胞免疫的效力和持久性。 了解环境如何调节人类T细胞库以影响后来的反应 它超越了疫苗的效力，与人类健康的许多领域广泛相关，包括感染， 自身免疫和癌症监测